In vitro metabolic products of RWJ-34130, an antiarrythmic agent, in rat liver preparations

The in vitro metabolism of RWJ-34130, an antiarrhythmic agent, was conducted using rat hepatic 9000 x g supernatant (S9) and microsomes in an NADPH-generating system, and the rat liver perfusion. The 100 and 20 microg ml(-1) concentrations of RWJ-34130 aqueous solution were used for microsomal incub...

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Bibliographic Details
Published in:Journal of pharmaceutical and biomedical analysis 1999-08, Vol.20 (4), p.687-695
Main Authors: WU, W.-N, MCKOWN, L. A, YORGEY, K. A, PRITCHARD, J. F
Format: Article
Language:English
Subjects:
Amidines - analysis
Amidines - chemistry
Amidines - metabolism
Analysis
Animals
Anti-Arrhythmia Agents - analysis
Anti-Arrhythmia Agents - chemistry
Anti-Arrhythmia Agents - metabolism
Biological and medical sciences
Chromatography, High Pressure Liquid
General pharmacology
Imines - analysis
Imines - chemistry
Imines - metabolism
Indoles - analysis
Indoles - chemistry
Indoles - metabolism
Liver - metabolism
Male
Mass Spectrometry
Medical sciences
Microsomes, Liver - metabolism
Pharmacology. Drug treatments
Rats
Rats, Wistar
Safrole - analogs & derivatives
Safrole - analysis
Safrole - metabolism
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Summary:The in vitro metabolism of RWJ-34130, an antiarrhythmic agent, was conducted using rat hepatic 9000 x g supernatant (S9) and microsomes in an NADPH-generating system, and the rat liver perfusion. The 100 and 20 microg ml(-1) concentrations of RWJ-34130 aqueous solution were used for microsomal incubation and liver perfusion, respectively. Unchanged RWJ-34130 (approximately 77-78% of the sample in both S9 and microsomes) plus a major metabolite, RWJ-34130 sulfoxide (20% of the sample in both S9 and microsomes) were profiled, isolated and identified from both hepatic S9 and microsomal incubates (60 min) using HPLC and mass spectrometry (MS), and by comparison to a synthetic RWJ-34130 sulfoxide, which was synthesized by reacting RWJ-34130 with MCPBA (meta-chloroperoxy benzoic acid). No unchanged RWJ-34130 was detected in the 3 h liver perfusate, however, 1-phenyl-2-oxo-pyrrolidine was profiled, isolated and identified as a major hydrolyzed metabolite of liver perfusate. RWJ-34130 is not extensively metabolized in vitro in rat hepatic S9 and microsomes. All HPLC metabolic profiles of hepatic S9 and microsomal samples (30 min, 60 min) were qualitatively and nearly quantitatively identical.
ISSN:0731-7085
1873-264X
DOI:10.1016/S0731-7085(99)00074-6